Effectiveness of COVID-19 vaccination against school absenteeism in children and adolescents hospitalized with COVID-19.

BACKGROUND: COVID-19 vaccination has been recommended for children to protect them and to enable in-person educational and social activities. METHODS: We estimated COVID-19 vaccination effectiveness (VE) against school absenteeism in children 5-17 years old hospitalized from September 1, 2021 through May 31, 2023. Full vaccination was defined as two vaccine doses. RESULTS: We studied 231 children admitted to hospital with COVID-19, including 206 (89.2 %) unvaccinated/partially vaccinated and 25 (10.8 %) fully vaccinated. Unvaccinated/partially vaccinated children were absent from school for longer periods compared to fully vaccinated children (median absence: 14 versus 10 days; p-value = 0.05). Multivariable regression showed that full COVID-19 vaccination was associated with fewer days of absence compared to no/partial vaccination on average (adjusted relative risk: 0.77; 95 % CI: 0.61 to 0.98). COVID-19 VE was 50.7 % (95 % CI: -11.3 % to 78.2 %) for school absenteeism above the median duration of absenteeism. CONCLUSIONS: Full COVID-19 vaccination conferred protection against school absenteeism in hospitalized school-aged children with COVID-19.

SARS-CoV-2 seroprevalence among children in Greece during Omicron variant period.

The Omicron variant is associated with increased transmissibility, but evidence about the impact of Omicron in seropositivity of children is limited. This study aims to evaluate SARS-CoV-2 seroprevalence in children during the different variants' subperiods. A prospective multicenter seroprevalence study was conducted in 7 University public hospitals in Greece from November 2021 to August 2022 (3 subperiods: November 2021-February 2022, March 2022-May 2022, June 2022-August 2022). Children from different age groups, admitted to the hospital or examined in outpatient clinics for reasons other than COVID-19 were enrolled. Neutralizing antibodies (Nabs), anti-Spike (anti-S) and anti-nucleocapsid (anti-N) SARS-CoV-2 IgG in serum were evaluated. A total of 2127 children (males:57,2%; median age:4,8years) were enrolled. Anti-N IgG seropositivity increased from 17,8% in the first sub-period to 40,7% in the second sub-period and then decreased in the third sub-period (36,7%). Anti-S IgG seropositivity appeared to have an increasing trend over the study period, starting from 34,8% and reaching 80,7%. Children aged 1-4 years old have significantly higher anti-N IgG titers compared to children aged 0-1 years old (p < 0,001). Infants have significantly lower anti-S IgG titers compared to all other age groups (p < 0,001). Immunocompromised children and infants have the lowest seropositivity for NAbs.Conclusions During the Omicron period, seropositivity significantly increased, as a result of higher transmissibility. Neonates and infants have lower antibody titers compared to other age groups, while young children aged 1-4 years old present higher antibody titers, suggesting that this age group may mount a higher antibody response. Continuous surveillance seroprevalence studies are needed in children, in order to identify the true extent of SARS-CoV-2 and guide the planning of adequate public health measures.

WHAT IS KNOWN: • Seroprevalence surveys among children may be extremely useful, in order to properly monitor the immunity, either natural or acquired, through the quantification of IgG antibodies and to plan further immunization policies. • There are variations in the seroprevalence of COVID-19 between the different periods, according to the vaccination rates, the type of circulating variant and the transmissibility of the virus. • The Omicron variant is associated with increased transmissibility, but evidence about the impact of Omicron in seropositivity of children is limited. WHAT IS NEW: • In this large multicenter seroepidemiological study, SARS-CoV-2 seroprevalence rate in children is higher during the Omicron period in comparison to the previous pandemic waves, due to the high transmissibility of the virus and the increased rates of reinfection. • Neonates and infants have lower antibody titers compared to other age groups, while young children aged 1­4 years old present higher antibody titers, indicating that the children of this age group mount a higher antibody response. • This study provides essential information about immunity and the level of protection in the pediatric population, as neutralizing antibodies were evaluated, in addition to the anti-N and anti-S IgG antibodies.

Multisystem inflammatory syndrome in children (MIS-C): A nationwide collaborative study in the Greek population.

Multisystem inflammatory syndrome in children (MIS-C) is a rare but severe hyperinflammatory condition that may occur following SARS-CoV-2 infection. This retrospective, descriptive study of children hospitalized with multisystem inflammatory syndrome in children (MIS-C) in 12 tertiary care centers from 3/11/2020 to 12/31/2021. Demographics, clinical and laboratory characteristics, treatment and outcomes are described. Among 145 patients (95 males, median age 8.2 years) included, 123 met the WHO criteria for MIS-C, while 112 (77%) had serological evidence of SARS-CoV-2 infection. Fever was present in 99%, gastrointestinal symptoms in 77%, mucocutaneous involvement in 68% and respiratory symptoms in 28%. Fifty-five patients (38%) developed myocarditis, 29 (20%) pericarditis and 19 (13%) coronary aneurysms. Among the above cases 11/55 (20%), 1/29 (3.4%) and 5/19 (26.3%), respectively, cardiac complications had not fully resolved at discharge. Underlying comorbidities were reported in 18%. Median CRP value was 155 mg/l, ferritin 535 ng/ml, PCT 1.6 ng/ml and WBC 14.2 × 109/mm3. Most patients had elevated troponin (41.3%) and/or NT-pro-BNP (49.6%). Intravenous immunoglobulin plus corticosteroids were used in 117/145 (80.6%), monotherapy with IVIG alone in 13/145 (8.9%) and with corticosteroids alone in 2/145 (1.3%). Anti-IL1 treatment was added in 15 patients (10.3%). Thirty-three patients (23%) were admitted to the PICU, 14% developed shock and 1 required ECMO. Mortality rate was 0.68%. The incidence of MIS-C was estimated at 0.69/1000 SARS-CoV-2 infections. Patients who presented with shock had higher levels of NT-pro-BNP compared to those who did not (p < 0.001). Acute kidney injury and/or myocarditis were associated with higher risk of developing shock. CONCLUSION: MIS-C is a novel, infrequent but serious disease entity. Cardiac manifestations included myocarditis and pericarditis, which resolved in most patients before discharge. Timely initiation of immunomodulatory therapy was shown to be effective. NT-pro-BNP levels may provide a better prediction and monitoring of the disease course. Further research is required to elucidate the pathogenesis, risk factors and optimal management, and long-term outcomes of this clinical entity. WHAT IS KNOWN: • MIS-C is an infrequent but serious disease entity. • Patients with MIS-C present with multi-organ dysfunction, primarily involving the gastrointestinal and cardiovascular systems. WHAT IS NEW: • NT-pro-BNP levels may provide a better prediction and monitoring of the disease course. • Acute kidney injury and/or myocarditis were associated with higher risk of developing shock.

An IL-10/DEL-1 axis supports granulopoiesis and survival from sepsis in early life.

The limited reserves of neutrophils are implicated in the susceptibility to infection in neonates, however the regulation of neutrophil kinetics in infections in early life remains poorly understood. Here we show that the developmental endothelial locus (DEL-1) is elevated in neonates and is critical for survival from neonatal polymicrobial sepsis, by supporting emergency granulopoiesis. Septic DEL-1 deficient neonate mice display low numbers of myeloid-biased multipotent and granulocyte-macrophage progenitors in the bone marrow, resulting in neutropenia, exaggerated bacteremia, and increased mortality; defects that are rescued by DEL-1 administration. A high IL-10/IL-17A ratio, observed in newborn sepsis, sustains tissue DEL-1 expression, as IL-10 upregulates while IL-17 downregulates DEL-1. Consistently, serum DEL-1 and blood neutrophils are elevated in septic adult and neonate patients with high serum IL-10/IL-17A ratio, and mortality is lower in septic patients with high serum DEL-1. Therefore, IL-10/DEL-1 axis supports emergency granulopoiesis, prevents neutropenia and promotes sepsis survival in early life.

Title: Repeated implantation failure is associated with increased Th17/Treg cell ratio, during the secretory phase of the human endometrium.

Repeated implantation failure (RIF) is a significant limiting factor in assisted reproduction. Chronic endometrial inflammation has been noted in RIF women, therefore we sought to investigate the potential association of endometrial Th17/Treg ratio and endometrial inflammation in these cases. Endometrial pipelle biopsies were obtained from volunteers, 29 women with RIF (failure to achieve pregnancy following at least 3 transfers of high-grade embryos in IVF-cycles) and 27 fertile women (at least one child) in total, at the secretory phase of the menstrual cycle. Using tissues from 17 fertile and 18 RIF endometrial samples, stromal and immune cells were isolated and flow cytometry analysis was performed to determine Th17 and CD4+ CD25high FOXP3+ cell populations in endometrial stromal cell suspensions. Another group of tissues from 10 fertile and 11 RIF samples were used for mRNA expression levels of Treg and Th17-cell transcription factors, FOXP3 and RORγt respectively. Endometrial inflammatory mediators' mRNA expression was also analyzed. A statistically significant increase in protein flow cytometry analysis of Th17/Treg ratio (p ≤ 0.05) as well as a reduction in absolute Treg cells in the endometrium (p ≤ 0.05) was noted in women with RIF. Additionally, RNA analysis on the same set of women indicated RORγt/FOXP3 significantly increased in women with RIF compared to fertile ones (p ≤ 0.05). Finally, women with RIF exhibited significantly (p ≤ 0.05) elevated mRNA levels of pro-inflammatory mediators (ΤΝF-a, ΙL-6, IL-8 and CCl2). Women with RIF exhibit elevated Th17/Treg ratio, mostly due to endometrial Treg depletion, as well as a pro-inflammatory state in the endometrium.

Seroprevalence of anti-SARS-CoV-2 antibodies among children and their parents in Greece.

School closures were enforced as measures to restrain the COVID-19 pandemic, based on the assumption that young children may play a key role in SARS-CoV-2 spread. This study aims to determine the prevalence of SARS-CoV-2 IgG antibodies in children and corresponding parents, in order to improve surveillance and estimate the prevalence of asymptomatic or subclinical COVID-19 cases. A prospective multicenter study was conducted between March and June 2021 in Greece. Children admitted to the hospital or examined in outpatient clinics for reasons other than COVID-19 and their parents were tested for anti-Spike SARS-CoV-2 IgG in serum. A questionnaire about clinical and demographic data was completed. The study included 823 participants: 427 children and 396 corresponding parents. The overall seroprevalence was 16.4% in parents and 13.8% in children. Among families with ≥ 1 seropositive child or parent, the combination of a seropositive parent and a corresponding seronegative child was 29.6%, a seronegative parent and a corresponding seropositive child was 24.7%, and a seropositive child with a corresponding seropositive parent was 45.7%. Age, level of education, and school or work attendance were not significantly associated with increased seropositivity. On the contrary, ethnic minority of Roma, close contact with known COVID-19 case, previous symptoms consistent with COVID-19, and mass gatherings were risk factors for seropositivity. CONCLUSION: The spread of SARS-CoV-2 during a period of lockdown in Greece was low in children and comparable to adults most likely due to intrafamilial transmission. Accordingly, it is unlikely that children have boosted virus transmission. WHAT IS KNOWN: • In the earliest months of the pandemic, it was demonstrated that children had significantly lower seroprevalence rates than the older age groups, due to the fact that children had decreased exposure to the virus, because of early public health interventions, such as school and day care closure. • Later, further studies reported that children have similar incidence rate of SARS-CoV-2 infection compared to adults in households and community settings. WHAT IS NEW: • In this seroprevalence study, the spread of SARS-CoV-2 infection during a period of lockdown in Greece with the predominance of the Alpha-variant was particularly low in children and comparable to adults, most likely due to intrafamilial transmission. • These study findings will be useful for decisions regarding non-pharmaceutical interventions during the pandemic, and especially, to guide in designing and implementing appropriate containment measures for schools and social gatherings.

The Psychological Impact of COVID-19 Admission on Families: Results from a Nationwide Sample in Greece.

The aim of the present study was to assess the psychological impact of hospitalization during the COVID-19 pandemic on parents and their offspring. We performed a nationwide cross-sectional study in Greece based on an Internet questionnaire survey. A convenience sample of parents whose offspring had been hospitalized due to COVID-19 (including multisystem inflammatory syndrome in children, MIS-C), diagnosed with COVID-19 but not hospitalized, and hospitalized for another reason during the pandemic were enrolled. Parental stress was assessed using the Perceived Stress Scale (PSS) and the Revised Impact of Event Scale (IES-R) tools, and childhood mental wellbeing with the Children's Revised Impact of Event 13 (CRIES-13) scale. Out of 214 received responses, stress levels were significantly higher in parents whose children had been admitted for COVID-19 or MIS-C versus those not admitted or admitted for other reasons (p < 0.001, for PSS/IES-R). Parental and childhood stress levels were correlated. In the multivariable linear regression analysis, children's hospitalization because of COVID-19 or MIS-C, younger parental age, the existence of comorbidities, and another family member's hospitalization because of COVID-19 were independent factors for higher stress. In light of the above, stricter hospital admission criteria for COVID-19 could be implemented, and psychological support for eventually admitted families may be beneficial.

SARS-CoV-2 modulates inflammatory responses of alveolar epithelial type II cells via PI3K/AKT pathway.

Background: SARS-CoV-2 infects through the respiratory route and triggers inflammatory response by affecting multiple cell types including type II alveolar epithelial cells. SARS-CoV-2 triggers signals via its Spike (S) protein, which have been shown to participate in the pathogenesis of COVID19. Aim: Aim of the present study was to investigate the effect of SARS-CoV2 on type II alveolar epithelial cells, focusing on signals initiated by its S protein and their impact on the expression of inflammatory mediators. Results: For this purpose A549 alveolar type II epithelial cells were exposed to SARS CoV2 S recombinant protein and the expression of inflammatory mediators was measured. The results showed that SARS-CoV-2 S protein decreased the expression and secretion of IL8, IL6 and TNFα, 6 hours following stimulation, while it had no effect on IFNα, CXCL5 and PAI-1 expression. We further examined whether SARS-CoV-2 S protein, when combined with TLR2 signals, which are also triggered by SARS-CoV2 and its envelope protein, exerts a different effect in type II alveolar epithelial cells. Simultaneous treatment of A549 cells with SARS-CoV-2 S protein and the TLR2 ligand PAM3csk4 decreased secretion of IL8, IL6 and TNFα, while it significantly increased IFNα, CXCL5 and PAI-1 mRNA expression. To investigate the molecular pathway through which SARS-CoV-2 S protein exerted this immunomodulatory action in alveolar epithelial cells, we measured the induction of MAPK/ERK and PI3K/AKT pathways and found that SARS-CoV-2 S protein induced the activation of the serine threonine kinase AKT. Treatment with the Akt inhibitor MK-2206, abolished the inhibitory effect of SARS-CoV-2 S protein on IL8, IL6 and TNFα expression, suggesting that SARS-CoV-2 S protein mediated its action via AKT kinases. Conclusion: The findings of our study, showed that SARS-CoV-2 S protein suppressed inflammatory responses in alveolar epithelial type II cells at early stages of infection through activation of the PI3K/AKT pathway. Thus, our results suggest that at early stages SARS-CoV-2 S protein signals inhibit immune responses to the virus allowing it to propagate the infection while in combination with TLR2 signals enhances PAI-1 expression, potentially affecting the local coagulation cascade.

Akt Inhibition Promotes Autophagy and Clearance of Group B Streptococcus from the Alveolar Epithelium.

Group B Streptococcus (GBS) is a gram-positive bacterium that is harmless for healthy individuals but may provoke invasive disease in young infants and immunocompromised hosts. GBS invades the epithelial barriers to enter the bloodstream, and thus strategies that enhance epithelial cell responses may hamper GBS invasion. In the present study, we sought to investigate whether the inhibition of Akt, a kinase that regulates host inflammatory responses and autophagy via suppression of mTOR, can enhance the response of non-phagocytic alveolar epithelial cells against GBS. Treatment of the alveolar epithelial cell line A549 with the Akt inhibitor MK-2206 resulted in the enhanced production of reactive oxygen species and inflammatory mediators in response to GBS. Additionally, Akt inhibition via MK-2206 resulted in elevated LC3II/I ratios and increased autophagic flux in alveolar epithelial cells. Importantly, the inhibition of Akt promoted GBS clearance both in alveolar epithelial cells in vitro and in lung tissue in vivo in a murine model of GBS pneumonia. The induction of autophagy was essential for GBS clearance in MK-2206 treated cells, as knockdown of ATG5, a critical component of autophagy, abrogated the effect of Akt inhibition on GBS clearance. Our findings highlight the role of Akt kinase inhibition in promoting autophagy and GBS clearance in the alveolar epithelium. The inhibition of Akt may serve as a promising measure to strengthen epithelial barriers and prevent GBS invasion in susceptible hosts.

AKT Isoforms in Macrophage Activation, Polarization, and Survival.

Macrophages display an array of activation phenotypes depending on the activation signal and the cellular microenvironment. The type and magnitude of the response depend on signaling molecules as well as on the epigenetic and metabolic status of the cells at the time of activation. The AKT family of kinases consists of three isoforms encoded by independent genes possessing similar functions and structures. Generation of research tools such as isoform-specific gene deletion mutant mice and cells and isoform-specific antibodies has allowed us to understand the role of each kinase isoform in macrophage activation and homeostasis. This chapter discusses the current evidence on the role of AKT kinases in macrophage activation, polarization, and homeostasis, highlighting the gaps in knowledge and future challenges in the field.

Mesenteric Lymphadenitis Presenting as Acute Abdomen in a Child with Multisystem Inflammatory Syndrome.

Multisystem inflammatory syndrome in children (MIS-C) may develop as a rare complication following COVID-19. MIS-C presentation varies substantially, but fever and gastrointestinal symptoms are the most prominent. Indeed, gastrointestinal involvement may be severe enough to present as acute abdomen, posing challenges to clinicians. We present herein the case of a healthy five-year-old male who presented with fever, vomiting, and abdominal pain, resembling acute abdomen. The patient had no history of SARS-CoV-2 infection or exposure, and MIS-C diagnosis was initially surpassed unnoticed. The patient underwent exploratory laparotomy that only revealed mesenteric lymphadenitis. Postoperatively, the patient met the clinical and laboratory diagnostic criteria of MIS-C. SARS-CoV-2 exposure was serologically confirmed and MIS-C treatment was commenced, resulting in defervescence and a satisfactory outcome. In young patients presenting with acute abdomen, surgeons should be aware of MIS-C, so that earlier diagnosis and appropriate treatment are made prior to surgical interventions.

Mild coronary artery dilatation developed in some children with mild COVID-19 but completely regressed within 3 months.

AIM: We studied the incidence and time course of any coronary artery changes in children up to 2 years of age who were hospitalised with mild COVID-19. METHODS: This was a single-centre prospective study of 29 children (19 males) with a median age of 3 months and interquartile range (IQR) of 1.6-4.3 months. They were admitted to a Greek University hospital for mild COVID-19 from 1 March to 30 December 2021. Three echocardiographic evaluations were performed at a median (IQR) of 19 (16-24) days, 82 (75-89) days and 172 (163-197) after the first symptoms. The prevalence of coronary artery dilation, regression, and changes was documented. RESULTS: Coronary artery dilation was present in 3 (10.3%) cases at the first evaluation, with complete regression at the second. Regression was observed in 18/24 (75%) cases with follow-up data and 9 (31%) demonstrated significant z-score changes of >2. Coronary artery changes in any segment at any time were documented in 18/29 (62%) of the patients. CONCLUSION: Cases of transient and very mild coronary artery dilatation following mild COVID-19 completely regressed within 3 months. Large-scale studies are needed to document the extent and time course of coronary artery dilation following paediatric COVID-19.

Infectious Diseases Associated with Desert Dust Outbreaks: A Systematic Review.

BACKGROUND: Desert dust outbreaks and dust storms are the major source of particulate matter globally and pose a major threat to human health. We investigated the microorganisms transported with desert dust particles and evaluated their potential impact on human health. METHODS: A systematic review of all reports on the association between non-anthropogenic desert dust pollution, dust microorganisms and human health is conducted. RESULTS: In total, 51 articles were included in this review. The affected regions studied were Asia (32/51, 62.7%) followed by Europe (9/51, 17.6%), America (6/51, 11.8%), Africa (4/51, 7.8%) and Australia (1/51, 2.0%). The Sahara Desert was the most frequent source of dust, followed by Asian and American deserts. In 39/51 studies the dust-related microbiome was analyzed, while, in 12/51 reports, the association of desert dust with infectious disease outbreaks was examined. Pathogenic and opportunistic agents were isolated from dust in 24/39 (61.5%) and 29/39 (74.4%) of the studies, respectively. A significant association of dust events with infectious disease outbreaks was found in 10/12 (83.3%) reports. The infectious diseases that were mostly investigated with dust outbreaks were pneumonia, respiratory tract infections, COVID-19, pulmonary tuberculosis and coccidioidomycosis. CONCLUSIONS: Desert dust outbreaks are vehicles of a significant number of pathogenic or opportunistic microorganisms and limited data indicate an association between dust events and infectious disease outbreaks. Further research is required to strengthen the correlation between dust events and infectious diseases and subsequently guide preventive public health measures.

Abnormal gait and hypoglycorrhachia in a toddler with seizures.

Introduction: Glucose transporter type 1 (Glut1) deficiency syndrome is a treatable neurometabolic disorder characterized by seizures, developmental delay, and hypoglycorrhachia. Due to the rareness and non-specific clinical manifestations, it is usually mis- or underdiagnosed. Case presentation: We report the case of a toddler who presented with afebrile epileptic seizures and abnormal gait. Brain imaging and electroencephalogram were normal. Further investigation of the cerebrospinal fluid revealed hypoglycorrhachia that was the clue to the diagnosis of Glut1 deficiency syndrome and the initiation of treatment with ketogenic diet. Conclusion: Our case highlights the importance of lumbar puncture while investigating a child with epileptic seizures and abnormal gait or developmental delay, in order not to miss treatable neurometabolic conditions, such as Glut1 deficiency syndrome.

Attitudes of junior healthcare professionals towards mandatory vaccination.

Vaccination of healthcare professionals (HCPs) is a key measure to prevent infections in healthcare facilities, but uptake rates often remain low. Mandatory vaccination policies have been occasionally implemented to increase compliance among HCPs, but this remains an issue of controversy. The purpose of this survey was to assess the attitudes and beliefs of trainee HCPs towards mandatory occupational vaccination and further explore the factors that determine their decision. In this cross-sectional survey, trainees consisted of medical residents and medical and nursing students undergoing their clinical clerkship. An anonymous questionnaire was distributed following pilot testing. In total, 410 trainees participated (response rate: 90.1%), of whom 194 (47.3%) were residents, 154 (37.6%) medical and 62 (15.1%) nursing students. Most participants (320/410, 78%) supported mandatory occupational vaccination, stating that it should be applied to promote public welfare and benefit (294/320, 91.9%) or should be a prerequisite for employment (271/320, 84.7%). Only 22/410 (5.4%) of HCPs opposed to mandatory occupational vaccination. The primary reasons for a negative attitude were the belief that personal rights outweigh public benefit (10/22, 45.5%) and the fear of side effects (9/22, 40.9%). Univariate analysis revealed that HCPs that have been informed by vaccination campaigns or had higher knowledge scores, were more likely to support mandatory occupational vaccination (OR 1.7, 95% CI: 1.1-2.7, p 0.038 and OR 1.7, 95% CI: 1.02- 2.7. p 0.044, respectively). In conclusion, most medical and nursing trainees in this study supported mandatory vaccination for HCPs. Focusing on continuing professional education on vaccines is important to positively determine HCPs' attitudes towards occupational vaccination and increase their vaccination uptake rates.

Challenges in the Diagnosis of Viral Encephalitis in Children: The Case of Two Siblings.

Encephalitis in children may lead to adverse outcomes and long-term neurodevelopmental sequelae. The prompt identification of the causative agent is important to guide proper management in cases with encephalitis; however, the etiology often remains undetermined. The use of polymerase chain reaction (PCR) analysis in the cerebrospinal fluid (CSF) has increased the diagnostic yield in encephalitis cases; however, it may be occasionally misleading. In this article, we describe the case of a male immunocompetent child with encephalitis in which human herpesvirus-7 (HHV-7) was detected in CSF by PCR. As the detection of HHV-7 DNA in the CSF alone is insufficient to prove an etiologic association of severe encephalitis in immunocompetent children, alternative diagnoses were pursued. Enterovirus (E-11) was detected by PCR analysis of the nasopharyngeal and rectal swabs of the male patient. The final diagnosis was facilitated by the findings in his sibling, which presented concurrently with enteroviral encephalitis. Failure to detect enterovirus in the CSF by PCR does not exclude enteroviral encephalitis; screening of other samples, from other body sites, may be necessary to identify the virus, and physicians should take into consideration all evidence, including history, clinical presentation, and sick contacts' clinical status.

Acute abdomen in multisystem inflammatory syndrome in children: A systematic review.

AIM: Multisystem inflammatory syndrome in children (MIS-C), a rare severe complication of SARS-CoV-2 infection, has been recently reported to mimic acute abdomen and lead to surgical interventions, posing challenges for clinicians. In this systematic review, we evaluated the rate of acute abdomen and abdominal surgical emergencies in children with MIS-C. METHODS: Systematic review of all MIS-C cases presented with acute abdomen. RESULTS: A total of 385 patients with MIS-C, from 38 studies, were included. Gastrointestinal manifestations were prominent in 233/385 (60.5%) children. Acute abdomen was noted in 72/385 (18.7%) of MIS-C cases and in 72/233 (30.9%) of MIS-C cases with gastrointestinal symptoms. Final diagnoses were mostly non-surgical (55/72, 76.4%), such as mesenteric lymphadenitis (23/72, 31.9%), terminal ileitis/ileocolitis (19/72, 26.4%), free abdominal fluid/ascites (8/72, 11.1%) and paralytic ileus (3/72, 4.2%). Laparotomy was performed in 35/72 (48.6%) of children with MIS-C, and acute abdomen and was proven unnecessary in 18/35 (51.4%) cases. True abdominal surgical emergencies, such as appendicitis and obstructive ileus, were confirmed in 17/72 (23.6%) cases. CONCLUSION: MIS-C often presents with acute abdomen, mostly due to non-surgical intestinal inflammatory pathology. However, surgical complications occur in patients with MIS-C; therefore, a high index of suspicion should remain.

Metabolic Regulation of Macrophage Activation.

Macrophages, the central mediators of innate immune responses, being in the first-line of defense, they have to readily respond to pathogenic or tissue damage signals to initiate the inflammatory cascade. Such rapid responses require energy to support orchestrated production of pro-inflammatory mediators and activation of phagocytosis. Being a cell type that is present in diverse environments and conditions, macrophages have to adapt to different nutritional resources. Thus, macrophages have developed plasticity and are capable of utilizing energy at both normoxic and hypoxic conditions and in the presence of varying concentrations of glucose or other nutrients. Such adaptation is reflected on changes in signaling pathways that modulate responses, accounting for the different activation phenotypes observed. Macrophage metabolism has been tightly associated with distinct activation phenotypes within the range of M1-like and M2-like types. In the context of diseases, systemic changes also affect macrophage metabolism, as in diabetes and insulin resistance, which results in altered metabolism and distinct activation phenotypes in the adipose tissue or in the periphery. In the context of solid tumors, tumor-associated macrophages adapt in the hypoxic environment, which results in metabolic changes that are reflected on an activation phenotype that supports tumor growth. Coordination of environmental and pathogenic signals determines macrophage metabolism, which in turn shapes the type and magnitude of the response. Therefore, modulating macrophage metabolism provides a potential therapeutic approach for inflammatory diseases and cancer.

SARS-CoV-2/ACE2 Interaction Suppresses IRAK-M Expression and Promotes Pro-Inflammatory Cytokine Production in Macrophages.

The major cause of death in SARS-CoV-2 infected patients is due to de-regulation of the innate immune system and development of cytokine storm. SARS-CoV-2 infects multiple cell types in the lung, including macrophages, by engagement of its spike (S) protein on angiotensin converting enzyme 2 (ACE2) receptor. ACE2 receptor initiates signals in macrophages that modulate their activation, including production of cytokines and chemokines. IL-1R-associated kinase (IRAK)-M is a central regulator of inflammatory responses regulating the magnitude of TLR responsiveness. Aim of the work was to investigate whether SARS-CoV-2 S protein-initiated signals modulate pro-inflammatory cytokine production in macrophages. For this purpose, we treated PMA-differentiated THP-1 human macrophages with SARS-CoV-2 S protein and measured the induction of inflammatory mediators including IL6, TNFα, IL8, CXCL5, and MIP1a. The results showed that SARS-CoV-2 S protein induced IL6, MIP1a and TNFα mRNA expression, while it had no effect on IL8 and CXCL5 mRNA levels. We further examined whether SARS-CoV-2 S protein altered the responsiveness of macrophages to TLR signals. Treatment of LPS-activated macrophages with SARS-CoV-2 S protein augmented IL6 and MIP1a mRNA, an effect that was evident at the protein level only for IL6. Similarly, treatment of PAM3csk4 stimulated macrophages with SARS-CoV-2 S protein resulted in increased mRNA of IL6, while TNFα and MIP1a were unaffected. The results were confirmed in primary human peripheral monocytic cells (PBMCs) and isolated CD14+ monocytes. Macrophage responsiveness to TLR ligands is regulated by IRAK-M, an inactive IRAK kinase isoform. Indeed, we found that SARS-CoV-2 S protein suppressed IRAK-M mRNA and protein expression both in THP1 macrophages and primary human PBMCs and CD14+ monocytes. Engagement of SARS-CoV-2 S protein with ACE2 results in internalization of ACE2 and suppression of its activity. Activation of ACE2 has been previously shown to induce anti-inflammatory responses in macrophages. Treatment of macrophages with the ACE2 activator DIZE suppressed the pro-inflammatory action of SARS-CoV-2. Our results demonstrated that SARS-CoV-2/ACE2 interaction rendered macrophages hyper-responsive to TLR signals, suppressed IRAK-M and promoted pro-inflammatory cytokine expression. Thus, activation of ACE2 may be a potential anti-inflammatory therapeutic strategy to eliminate the development of cytokine storm observed in COVID-19 patients.

Extensive Cellulitis and Bacteremia Due to Streptococcus Pseudoporcinus in a Child With Klippel-Trenaunay Syndrome.

Streptococcus pseudoporcinus is a newly recognized ß-hemolytic streptococcus, that is considered a rare pathogen in adults. Infections in children have not been reported. We describe a child with Klippel-Trenaunay syndrome that developed of S. pseudoporcinus cellulitis and bacteremia, which was difficult-to-treat, relapsed and required prolonged antibiotic courses. S. pseudoporcinus can cause invasive infection in children, especially in the presence of predisposing conditions.